Autism Spectrum Disorder (ASD) is a developmental disorder characterized by restricted interest and communication impairment generated by genetic and environmental factors. The delivery period is instrumental in the pathogenesis of autism with complications during delivery and/or cesarean sections enhancing its incidence (Hultman et al. Epidemiology 13, 417 (2002); Guinchat et al., Acta Obstetricia et Gynecologica Scandinavica 91, 287 (2012)). Also, alterations of oxytocin signals that trigger labor and are instrumental for communication notably parental/infant interactions favor autism (Pobbe et al. Hormones and Behavior 61, 436 (2012)). Yet, in spite of these observations, the properties of immature autistic neurons before and shortly after delivery are presently unknown.
Brain maturation is associated with a developmental sequential expression of voltage gated, receptor synapse driven channels and brain patterns (Spitzer et al., 1994; Ben Ari et al., 2007). The developmental shifts of the actions of the inhibitory transmitter GABA is but one example of these changes. Immature neurons have a higher intracellular chloride concentration (Cl−)I than adults leading to paradoxical excitatory actions of GABA (Ben Ari et al., Nat Rev Neurosci. 2002 September; 3(9):728-39; Ben Ari et al., Physiol Rev. 2007 October; 87(4):1215-84). This is due to an early expression of the co-transporter NKCC1 that imports chloride and a late operation of KCC2 that export chloride form neurons (Ben Ari et al., Nat Rev Neurosci. 2002 September; 3(9):728-39). In addition, the regulation of (Cl−)I is dynamic and altered by even brief episodes of enhanced activity and more persistently by a variety of insults, lesions, seizures and neurological disorders (Khalilov I et al. (2003) Nat Neurosci 6:1079-1085; Khalilov I et al. (2005) 48:787-796).
The applicant already disclosed the use of NKCC inhibitors for the treatment of autism in children (WO2011/086126) but surprisingly, the inventors also discovered that treating a fetus before delivery or a baby could also treat ASD.
Indeed, the applicant characterized for the first time the cellular and network alterations that occur during the transition from fetal to post natal life and subsequently in an animal model of autism: the Valproate in utero model (VPA). The applicants' results stress the importance of events during delivery in the pathogenesis of autism and suggest that early diagnosis combined with the treatment with a modulator of chloride importation will be instrumental in preventing the deleterious cycle leading to autism.